tbuckley/cabot-search huggingface dataset:
Abstract 1677: ASPC-1-MRTX-1133R as a useful cell line model for KRAS-G12D inhibitor development
Authors: Guoqian Wang, Yao Tang, Tingduo Lv, Jinying Ning, Feng Hao
Journal: Cancer Research (2023)

Abstract Introduction: KRAS mutations occur in nearly 30% of human cancers, the most frequent ones being G12C, G12D and G12V. The approval of AMG510 in 2021 broke the curse of KRAS’s non-druggability. AMG510 targets the KRAS-G12C mutation and achieves up to 90% disease control rate, but drug resistance quickly develops. KRAS-G12D, the most prevalent and oncogenic KRAS mutation, still lacks inhibitors. MRTX-1133, the first reported highly selective KRAS-G12D inhibitor, is currently in the preclinical phase. Similarly, drug resistance will inevitably develop to KRAS-G12D inhibitors. Methods: To explore the resistance mechanisms of KRAS-G12D mutation, our group used ASPC-1 cell line, which naturally expresses KRAS-G12D, to generate the ASPC-1-MRTX-1133R cell line using a dose-escalation method after treating cells with a mutagenic agent. Specifically, ASPC-1 cells were treated by MRTX-1133 with increasing dosage for 4 weeks, the remaining live cells were harvested and designated as ASPC-1-MRTX-1133R. Cell survival assay showed that IC50 of ASPC-1-MRTX-1133R is &amp;gt;2000nM, 100-fold more resistant than the parental ASPC-1 cell line (22nM). We identified the potential resistance mechanisms using whole exome sequencing (WES) and RNA-Seq. The resistance to MRTX-1133 of ASPC-1-MRTX-1133R cell line was highly stable after 20 cell passages. Conclusion: The ASPC-1-MRTX-1133R cell line can be a useful in vitro model in the development of KRAS-G12D inhibitors. Citation Format: Guoqian Wang, Yao Tang, Tingduo Lv, Jinying Ning, Feng Hao. ASPC-1-MRTX-1133R as a useful cell line model for KRAS-G12D inhibitor development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1677.
Abstract 3830: The anticancer activity of a water-soluble extract from the leaves of the indigenous Southern African plant <i>Tulbaghia violacea</i> against a triple negative breast cancer cell line
Authors: Rodney Hull, Zodwa Dlamini, Clement Penny, Mohammed Alaouna
Journal: Cancer Research (2023)

Abstract Triple negative breast cancer (TNBC) is difficult to treat and leads to a low five-year survival rate.In South Africa, a sizable percentage of the population still relies on traditional plant-based medicine. One of these plants, Tulbaghia violacea), has traditionally been used to treat cancer. In order to establish the usefulness of both methanol and water-soluble extracts from the leaves of this plant, extracts were used to treat a TNBC cell. Cytotoxicity assays were carried out to establish the IC50 values against the TNBC cell line. These concentrations were used to carry out assays to study the ability of these extracts to inhibit cell migration, invasion, as well as the effect of these extracts on the cell cycle and their ability to induce apoptosis in these cells. Finally, the antioxidant activity of these cells was assayed. The IC50 values for the water and methanol soluble extracts was determined to be 400 and 820 µg/mL respectively. Due to the high IC50 value and inconsistent performance of the methanol soluble extract, further studies focussed on the water-soluble extract. Treatment of the TNBC cells with the water-soluble extract led to an increase in apoptosis, with the extract causing approximately 82% of the TNBC cells to undergo apoptosis compared to only 32% of the normal breast cells. This extract also significantly decreased the ability of the TNBC cells to migrate or penetrate abasement membrane in scratch and invasion assays. These results demonstrate that the water-soluble extract from T. violacea leaves contains compounds that are able to preferentially induce apoptosis in TNBC cells while also inhibiting the ability of these cells to metastasize. The exact molecular make up of this extract will need to be determined on order to develop the extract as a potential therapy for TNBC. Citation Format: Rodney Hull, Zodwa Dlamini, Clement Penny, Mohammed Alaouna. The anticancer activity of a water-soluble extract from the leaves of the indigenous Southern African plant Tulbaghia violacea against a triple negative breast cancer cell line. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3830.
Abstract 178: Establishment of patient-derived organoid of breast cancer
Authors: Won-Ji Ryu, Shinyoung Park, Jeong Dong Lee, Yumi Hwang, Seongyeon Jo, Kweon Tae Yong, Ja Seung Koo, Min Hwan Kim, Joo Hyuk Sohn, Hyung Seok Park
Journal: Cancer Research (2023)

Abstract A patient-derived organoid (PDO) is an in vitro three-dimensional model which shows similar features in phenotypic and genetic aspects with primary tissue from patients. PDOs are useful for preclinical studies including drug sensitivity tests of tumors from individual patients as well as development of novel targeted agents. Collectively, PDOs are recently introduced as an emerging platform for personalized medicine. We obtained a total of 100 surgical specimens from 100 patients with breast cancer at the Yonsei Cancer Center, Severance Hospital, Seoul, Korea. One of the tissue specimens was acquired from a breast cancer patient-derived xenograft model. We dissociated the tissues and isolated breast cancer primary tumor cells from the samples, and then the cells were cultured in basement membrane-like matrix in 3D manner with growth medium with supplements. We defined successful establishment of PDOs as continuous growth after 3 passaging. Among all 100 cases, 32 cases failed to culture or passage, however, 41 cases were successfully cultured over 3 passages. In addition, the remaining 27 cases are still in progress of establishment. Success rate of PDO was 68% (68/100). Subtypes of primary tumors of the PDO were 33.8% (23/68) of luminal A, 26.5% (18/68) of luminal B, 26.5% (18/68) of triple-negative, 5.9% (4/68) of triple-positive and 7.4% (5/68) of HER2-enriched. Success rates of each subtype were 69.7% (23/33) of luminal A, 72.0% (18/25) of luminal B, 66.7% (18/27) of triple-negative, 66.7% (4/6) of triple-positive and 55.6% (5/9) of HER2-enriched. Pathologic evaluation using immunohistochemistry revealed that PDOs showed similar morphologic and immunohistochemical features with primary tumors. The selective sensitivity of PARP inhibitor, olaparib, was confirmed in PDOs harboring mutant BRCA1/2 compared with BRCA1/2 wild-type PDOs. Overall, PDOs can be used as a real-time platform for drug sensitivity and screening analyses, and a robust tool for preclinical studies in breast cancer. Citation Format: Won-Ji Ryu, Shinyoung Park, Jeong Dong Lee, Yumi Hwang, Seongyeon Jo, Kweon Tae Yong, Ja Seung Koo, Min Hwan Kim, Joo Hyuk Sohn, Hyung Seok Park. Establishment of patient-derived organoid of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 178.
Abstract 3068: CREBBP/EP300 disruption promotes tumor progression and confers synthetic lethality in anaplastic thyroid cancers
Authors: Jacob Haase, Talia A. Gebhard, Qi Liu, Sara G. Bernabé, Jingzhu Hao, Chisom Unegbu, Athanasios Bikas, Jun Qi, Iñigo Landa
Journal: Cancer Research (2023)

Abstract Anaplastic thyroid cancers (ATC) are fast-growing, undifferentiated tumors and almost invariably fatal, primarily due to the lack of effective therapeutic options. The recent approval of dabrafenib plus trametinib for the treatment of BRAFV600E-mutant ATCs improved the prognosis of a subset of patients, but ineligibility and acquired resistance still limit their use. Overall, ATC patients remain in great need of tailored therapeutic options. We previously showed that loss-of-function alterations targeting histone acetyltransferase (HAT) genes, namely CREBBP and EP300, occur in 15-20% of ATCs, but only in &amp;lt;1% of their well-differentiated counterparts. What remains unknown are the specific mechanisms by which HAT disruptions perturb chromatin architecture, impact gene homeostasis, and unleash cellular processes in these aggressive tumors. We are assessing the HAT-mediated thyroid cancer progression. CREBBP/EP300 knockouts enhanced thyroid cancer cell proliferation in vitro and induced thyroid gland growth in a thyroid-specific mouse model of HAT loss. We are leveraging these animals to characterize the in vivo effects of Crebbp/Ep300 knockout, alone or in combination with BrafV600E, in thyroid cancer phenotypes and epigenetic reconfiguration. In addition, we are exploiting the molecular consequences of HAT loss to explore tailored treatments. CRISPR/Cas9 screens identified a mutual CREBBP/EP300-dependency of HAT-mutant human cancer cell models. Our experiments in thyroid cancer cells employing CREBBP/EP300-targeting proteolysis-targeting chimera (PROTAC) compounds specifically degraded these proteins and decreased histone acetylation. Our findings prove the oncogenicity of HAT loss in thyroid cancer progression and support exploring synthetic lethality dependencies in CREBBP/EP300-mutant ATCs. In summary, we provide pre-clinical basis to inform genomics-driven and mechanism-oriented decisions for the clinical management of patients with HAT-altered ATC. Citation Format: Jacob Haase, Talia A. Gebhard, Qi Liu, Sara G. Bernabé, Jingzhu Hao, Chisom Unegbu, Athanasios Bikas, Jun Qi, Iñigo Landa. CREBBP/EP300 disruption promotes tumor progression and confers synthetic lethality in anaplastic thyroid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3068.
Abstract 6493: Ethnic disparities in breast cancer survival in Guam
Authors: Grazyna Badowski, Rodney Teria, Louis Dulana, Cabrini Aguon, Lynne Wilkens, Yurii Shvetsov, Rachel Novotny, Rachael T. Leon Guerrero
Journal: Cancer Research (2023)

Abstract Background: Breast cancer is the second leading cause of cancer-related death among women in Guam. The breast cancer mortality rate is higher in Guam than in the U.S. (27.3 vs 20.3 per 100,000 women, age-adjusted, 2013-2017 data); even though the incidence rate remains lower (86.6 vs 126.8 respectively). Guam has major ethnic disparities in breast cancer survival with CHamoru (indigenous people) and Micronesian (immigrants from other Micronesian Islands) faring much worse than other ethnic groups. The purpose of this study was to determine the survival rates of breast cancer patients in Guam and examine the effects of demographic and other mortality risk factors on breast cancer survival. Methods: This study included 1105 women diagnosed with primary invasive breast cancer and reported to the Guam Cancer Registry from 1998-2020. Five-year and 10-year survival rates were calculated using the Kaplan-Meier method and were compared using the log-rank test across different ethnic groups: CHamoru (N = 528), Filipino (N = 336), Asian (N = 66), Micronesian (N = 51), and Caucasian (N = 71). The Cox proportional hazards regression was used to investigate the effects of age, year of diagnosis, ethnicity, breast cancer staging, and cancer treatment status on the risk of all-cause mortality. Results: Mean age at diagnosis was 58.2 years. Significant differences in the 5-year and 10-year survival rates were found across ethnic groups. Micronesians had the lowest 5-year and 10-year survival rates (55.9% and 48.5%) followed by CHamorus (81.1% and 68.1%, respectively). All-cause mortality was higher among CHamoru (HR = 2.28, 95% CI: 1.65, 3.16) and Micronesian women (HR=5.33, 95% CI: 3.30, 8.61) compared with Filipino women after adjusting for age, year of diagnosis, staging, and cancer treatment status. All-cause mortality among White and Asian women was not statistically significantly different from that among Filipino women. Cancer staging also indicated significantly higher hazard rate for late-stage patients when compared to early-stage patients (HR = 3.62, 95% CI: 2.70, 4.85). Conclusion: The analysis suggests significant differences in breast cancer 5-year and 10-year survival rates across different ethnic groups, with Micronesian women exhibiting the highest hazard rate among women in Guam. Acknowledgement: This study was supported by the PIPCHE/U54 Grant (U54CA143728), a partnership between the University of Hawai'i Cancer Center and the University of Guam. Citation Format: Grazyna Badowski, Rodney Teria, Louis Dulana, Cabrini Aguon, Lynne Wilkens, Yurii Shvetsov, Rachel Novotny, Rachael T. Leon Guerrero. Ethnic disparities in breast cancer survival in Guam. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6493.
Abstract 1162: Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia
Authors: Miriam Ferrer, Nicholas Mourikis, Emma E. Davidson, Sam O. Kleeman, Marta Zaccaria, Jill Habel, Rachel Rubino, Thomas R. Flint, Claire M. Connell, Michael J. Lukey, Eileen P. White, Anthony P. Coll, Ashok R. Venkitaraman, Tobias Janowitz
Journal: Cancer Research (2023)

Abstract The dependency of cancer cells on glucose can be targeted with high-fat low-carbohydrate ketogenic diet (KD). However, hepatic ketogenesis is suppressed in IL-6 producing cancers, which prevents the utilization of this nutrient source as energy for the organism. In two IL-6 associated murine models of cancer cachexia we describe delayed tumor growth but accelerated onset of cancer cachexia and shortened survival when mice are fed KD. Mechanistically, we find this uncoupling is a consequence of the biochemical interaction of two simultaneously occurring NADPH-dependent pathways. Within the tumor, increased production of lipid peroxidation products (LPPs) and, consequently, saturation of the glutathione (GSH) system leads to ferroptotic death of cancer cells. Systemically, redox imbalance and NADPH depletion impairs the biosynthesis of corticosterone, the main regulator of metabolic stress, in the adrenal glands. Administration of dexamethasone, a potent glucocorticoid, improves food intake, normalizes glucose homeostasis and utilization of nutritional substrates, delays onset of cancer cachexia and extends survival of tumor-bearing mice fed KD, while preserving reduced tumor growth. Our study highlights that the outcome of systemic interventions cannot necessarily be extrapolated from the effect on the tumor alone, but that they have to be investigated for anti-cancer and host effects. These findings may be relevant to clinical research efforts that investigate nutritional interventions such as KD in patients with cancer. Citation Format: Miriam Ferrer, Nicholas Mourikis, Emma E. Davidson, Sam O. Kleeman, Marta Zaccaria, Jill Habel, Rachel Rubino, Thomas R. Flint, Claire M. Connell, Michael J. Lukey, Eileen P. White, Anthony P. Coll, Ashok R. Venkitaraman, Tobias Janowitz. Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1162.
Abstract 375: Smoking induces Wee1 expression through miRNA deregulation, promoting docetaxel resistance in esophageal adenocarcinoma
Authors: Krishnapriya Thangaretnam, Islam MD Obaidul, Heng Lu, Dunfa Peng, Nadeem Sidiq Bhat, Mohammed Soutto, Zheng Chen
Journal: Cancer Research (2023)

Abstract Esophageal Adenocarcinoma (EAC) is the most common subtype of Esophageal Cancer in Western countries, and its incidence rate has increased over the past few decades. The overall five-year survival rate of EAC is less than 20%. Smoking is a major risk factor for EAC development. WEE1 kinase plays a crucial role in the cell cycle by regulating the G2/M checkpoint, providing a time frame for the cells to repair DNA damage. Thus, targeting WEE1 using an inhibitor could potentiate the effect of chemotherapeutic drugs. This study investigated how smoking induces WEE1 protein expression, promoting docetaxel resistance in EAC. IHC staining for WEE1 in the normal esophagus and EAC tissue sections revealed significant over-expression of WEE1 protein in EAC. Nicotine, Nicotine derived Nitrosamine Ketone (NNK), and 2% cigarette smoke extract (CSE) treatment induced WEE1 expression with a concomitant increase in CDC2 phosphorylation (p-CDC2, Y15), a well-established read-out of WEE1 activity in EAC cells. In addition, we found that smoking upregulates WEE1 expression by decreasing miR-195-5p expression levels in EAC. Based on the differential gene expression signatures in EAC cell lines FLO1 and OE33 following WEE1 knockdown, drug and small molecule induced gene expression signatures analysis, L1000 fireworks display (L1000FWD), predicted that docetaxel is one of the best drug candidates which can synergize with the WEE1 inhibitor MK1775. Smoking-induced docetaxel resistance in EAC cells measured by cell viability assay. Down-regulating WEE1 expression with siRNA or pharmacological inhibition using MK1775 significantly sensitized EAC cells to docetaxel treatment, as evidenced by a remarkable decrease in the IC50 value of docetaxel. Inhibition of WEE1 combined with docetaxel can be considered an ideal therapeutic strategy due to its superior anti-tumor efficacy compared to the standard single-agent treatment. In conclusion, our data provide a firm rationale for the clinical combination of docetaxel with MK1775 in EAC patients. Citation Format: Krishnapriya Thangaretnam, Islam MD Obaidul, Heng Lu, Dunfa Peng, Nadeem Sidiq Bhat, Mohammed Soutto, Zheng Chen. Smoking induces Wee1 expression through miRNA deregulation, promoting docetaxel resistance in esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 375.
Abstract 1099: Combined treatment with direct hydrogen peroxide administration and irradiation promotes an abscopal effect in mouse models
Authors: Naoya Kemmotsu, Li zhu, Youki Ueda, Hiromichi Dansako, Shinichi Toyooka, Joji Nagasaki, Yosuke Togashi
Journal: Cancer Research (2023)

Abstract Background: Hydrogen peroxide (H2O2) causes oxidative stress and cytotoxicity and may be used in cancer therapy in combination with radiotherapy (RT). Indeed, H2O2 has been clinically developed as a radiosensitizer (development code: KRC-01). However, effects of H2O2 on antitumor immunity remain unclear. In this study, we investigated the effects, especially an abscopal effect, using mouse models. Material and Method: We used MC-38 (mouse colon cancer) and B16F10 (mouse melanoma) cell lines. Tumor cells were implanted simultaneously in two locations; hind legs and back of mice. A self-made radiation shielding device was used to prevent irradiation of the tumors on the back. Only the hind legs were directly injected with a mixture of H2O2 and hyaluronic acid (KRC-01), and then irradiated. Immune cells in tumors or tumor draining lymph nodes were analyzed with flow cytometry. Result: We compared tumor growth among four groups: control, irradiation alone, H2O2 alone, and combination groups. Compared to the other groups, the combination significantly reduced non-irradiated tumor growth (abscopal effect). In immunodeficient SCID mice, this effect was not observed. Flow cytometric analyses of tumor draining lymph nodes showed that dendritic cells were maturated in the combination groups compared to the others. In addition, CD8+ T cells were activated in the non-irradiated tumors from the combination group compared to the others. Conclusion: Intratumoral H2O2 administration enhanced the abscopal effect through activating antitumor immunity by RT. Citation Format: Naoya Kemmotsu, Li zhu, Youki Ueda, Hiromichi Dansako, Shinichi Toyooka, Joji Nagasaki, Yosuke Togashi. Combined treatment with direct hydrogen peroxide administration and irradiation promotes an abscopal effect in mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1099.
Abstract 1293: GPRC5A drives an implantation-like phenotype in early-stage lung disseminated cancer cells of esophageal squamous carcinoma
Authors: Hongyu Zhou, Beilei Liu, Ching Ngar Wong, Xinyuan Guan
Journal: Cancer Research (2023)

Abstract Esophageal squamous carcinoma (ESCC) is one of the leading malignancies worldwide, especially in Asian countries, largely threatening human life. The 5-year survival rate of ESCC is less than 20%, and patients with distant metastases have dismal survival with &amp;lt;5% of five-year survival rate. Traditional therapies e.g., surgery, chemotherapy, radiotherapy demonstrate poor clinical outcomes for ESCC patients. Metastases are commonly seen in ESCC patients, and lung metastases approximately account for 5% of all ESCC metastases. The underlying mechanism of ESCC lung metastasis remains unsettled. In our study, we established ESCC lung metastasis mice model via intravenous injection of ESCC cells in multiple timepoints. Lung disseminated cancer cell (DCCs) of different timepoints were isolated and thrown into single cell RNA sequencing (scRNA-seq). Via bioinformatic analysis, we found the upregulated genes in early-stage lung DCCs were highly enriched in embryo development, placenta development, pre-implantation embryos processes, neither in late-stage lung DCCs. It highly suggested that ESCC lung metastasis process might be similar to embryo implantation. Based on above findings, 5 intersected genes (GPRC5A, FSTL3, WNT7A, TM4SF1, NT5E) of early-stage lung DCCs and embryo implantation were figured out to construct an implantation-like signature. Enrichment analysis results implied that ESCCs subgroups with implantation-like phenotype showed higher ability to migration, focal adhesion and response to stress. Preliminary data indicated that the representative gene GPRC5A was upregulated in ESCC tumors compared with normal esophageal epithelium in clinical samples and public databases. GPRC5A overexpression promoted tumor growth, invasion, migration and sphere formation both in vivo and in vitro, as the same as other two signature genes, WNT7A and FSTL3. Moreover, GPRC5A-overexpresssing ESCC cells displayed high ability to develop resistance to stress and generated less reactive oxygen species (ROS) in vitro. In vivo, GPRC5A overexpression increased the quantalities of early-stage lung DCCs in ESCC lung metastasis mice model and disruption of GPRC5A expression abolished its pro-metastatic effect. Together, our preliminary findings identify an implantation-like signature in early-stage ESCC lung metastasis and disrupting this phenotype helps to prevent ESCC tumorigenesis and metastasis. Citation Format: Hongyu Zhou, Beilei Liu, Ching Ngar Wong, Xinyuan Guan. GPRC5A drives an implantation-like phenotype in early-stage lung disseminated cancer cells of esophageal squamous carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1293.